Setidegrasib shows early promise in KRAS G12D-mutated lung and pancreatic cancers

In a phase 1 trial published in New England Journal of Medicine in March 2026, the investigational drug setidegrasib showed encouraging antitumor activity in patients with advanced cancers driven by the KRAS G12D mutation, including non-small cell lung cancer (NSCLC) and pancreatic ductal adenocarcinoma — two diseases where targeted options for this mutation have been notably absent.

“Setidegrasib is the first drug in this KRAS degrader class targeting KRAS G12D in solid tumors,” lead investigator Wungki Park, M.D., M.S., an oncologist at Memorial Sloan Kettering Cancer Center, said in a news release. “Rather than blocking the signal, setidegrasib removes the KRAS protein itself.”

KRAS mutations are among the most common drivers of cancer, but not all are equally druggable. The KRAS p.G12D variant appears in about 5% of NSCLC cases and roughly 40% of pancreatic cancers. Unlike KRAS G12C, it has remained difficult to target due to structural features that limit drug binding. Setidegrasib uses a different strategy by marking the mutant protein for degradation, which may help shut down cancer-related signaling more effectively.

The study, led by investigators across 28 centers in five countries, evaluated the safety and early efficacy of setidegrasib in 203 patients with previously treated, advanced KRAS G12D-mutated solid tumors. Patients received weekly intravenous doses ranging from 10 to 800 mg, with 600 mg selected as the recommended phase 2 dose based on its safety and activity profile.

Among patients with NSCLC treated at the 600-mg dose, results were particularly encouraging. Of 45 evaluable patients who had received at least one prior therapy, 36% experienced an objective response, all of which were partial responses. The median progression-free survival was 8.3 months, and the estimated overall survival at 12 months was 59%. In a subset receiving the drug as second- or third-line therapy, response rates were similar at 38%, with a longer median progression-free survival of 11.2 months.

These outcomes compare favorably with existing second-line treatments, which typically produce response rates between 9% and 23% and progression-free survival of about 3 to 4.5 months, according to the study authors.

Activity was also observed in pancreatic cancer, although outcomes were more modest. Among 21 patients with metastatic pancreatic ductal adenocarcinoma treated in the second- or third-line setting, 24% had a response. Median progression-free survival was 3 months, and median overall survival reached 10.3 months. Although limited, these results are notable given the lack of established third-line options and generally poor prognosis in this population.

Adverse events occurred in all patients receiving the 600-mg dose, with grade 3 or higher events in 42%. The most common treatment-related adverse events were infusion-related reactions (80%) and nausea (30%). Notably, infusion reactions were typically mild to moderate and were manageable with standard measures. Only two patients discontinued treatment due to adverse events.

“These findings highlight the clinical activity of setidegrasib and support its therapeutic potential in this molecularly defined population,” the authors wrote in their paper. They also pointed to a potential advantage of protein degradation over traditional inhibition.

The study’s early-phase design cannot establish definitive benefit or compare outcomes across treatments. Biomarker findings were exploratory, and it remains unclear which patients are most likely to respond. Still, the results offer an early signal that targeting KRAS G12D through protein degradation could open a new therapeutic avenue. The study was supported by the drug’s developer, Astellas Pharma Inc. The company is also sponsoring ongoing and planned clinical trials of setidegrasib, including combination studies.

Park described the drug’s potential as “exciting, because the trial results suggest that setidegrasib can not only extend life for some patients with these aggressive cancers, it also has a very good safety profile, meaning the drug was well-tolerated with side effects that can be managed quite easily.”